ORIGINAL ARTICLE

Diagnostic usefulness of an amino acid tracer,a-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB),in the PET diagnosis of chest malignancies

Ryuichi Nishii • Tatsuya Higashi • Shinya Kagawa • Yoshihiko Kishibe • Masaaki Takahashi • Hiroshi Yamauchi •

Hideki Motoyama • Kenzo Kawakami • Takashi Nakaoku • Jun Nohara • Misato Okamura • Toshiki Watanabe •

Koichi Nakatani • Shigeki Nagamachi • Shozo Tamura • Keiichi Kawai • Masato Kobayashi

Received: 27 May 2013 / Accepted: 17 June 2013 / Published online: 4 July 2013

� The Author(s) 2013. This article is published with open access at Springerlink.com

Abstract

Objectives Although positron emission tomography

(PET) using [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) is

established as one of the first-choice imaging modalities in

the diagnosis of chest malignancies, there are several

problems to solve in clinical practice, such as false positive

uptake in inflammatory diseases. The aim of this study was

to evaluate the clinical usefulness of an amino acid tracer,

a-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeA-

IB), in the diagnosis of chest malignancies, in combination

with 18F-FDG.

Setting Fifty-nine cases (57 patients, 66 ± 12 years old)

who consulted to our institution for the wish to receive

differential diagnosis of chest diseases were included.

Purpose of the studies were as follows: differential diag-

nosis of newly developed lung nodules, n = 22; newly

developed mediastinal lesions, n = 20; and both, n = 17

(including lung cancer: n = 19, lymphoma: n = 1, other

cancers: n = 2, sarcoidosis: n = 15, non-specific inflam-

mation: n = 18, other inflammatory: n = 4, respectively).

Whole-body static PET or PET/CT scan was performed 20

and 50 min after the IV injection of 11C-MeAIB and 18F-

FDG, respectively.

Results 11C-MeAIB uptake of malignant and benign

lesions was statistically different both in pulmonary nod-

ules (p \ 0.005) and in mediastinal lesions (p \ 0.0005).

In visual differential diagnosis, 11C-MeAIB showed higher

results (specificity: 73 %, accuracy: 81 %), compared to

those in 18F-FDG (60, 73 %, respectively). In cases of

sarcoidosis, 11C-MeAIB showed higher specificity (80 %)

with lower uptake (1.8 ± 0.7) in contrast to the lower

specificity (60 %) with higher uptake of 18F-FDG

(7.3 ± 4.5).

Conclusions 11C-MeAIB PET/CT was useful in the dif-

ferential diagnosis of pulmonary and mediastinal mass

lesions found on CT. 11C-MeAIB PET or PET/CT showed

higher specificity than that of 18F-FDG PET/CT in differ-

entiating between benign and malignant disease. Our data

suggest that the combination of 18F-FDG and 11C-MeAIB

may improve the evaluation of chest lesions, when CT and18F-FDG PET/CT are equivocal.

Keywords Amino acid tracer � Methylaminoisobutyric

acid � Fluorodeoxyglucose � Lung cancer �Lymphadenopathy � Positron emission tomography �Sarcoidosis

R. Nishii � T. Higashi (&) � S. Kagawa � Y. Kishibe �M. Takahashi � H. Yamauchi

Shiga Medical Center Research Institute, 5-4-30 Moriyama,

Moriyama, Shiga 524-8524, Japan

e-mail: higashi@res.med.shiga-pref.jp

R. Nishii � S. Nagamachi � S. Tamura

Department of Radiology, Faculty of Medicine, Miyazaki

University, 5200 Kihara, Kiyotake-cho,

Miyazaki, Miyazaki 889-1692, Japan

H. Motoyama � K. Kawakami

Department of Thoracic Surgery, Shiga Medical Center, 5-4-30

Moriyama, Moriyama, Shiga 524-8524, Japan

T. Nakaoku � J. Nohara � M. Okamura � T. Watanabe �K. Nakatani

Department of Respiratory Medicine, Shiga Medical Center,

5-4-30 Moriyama, Moriyama, Shiga 524-8524, Japan

K. Kawai � M. Kobayashi

Division of Health Sciences, Graduate School of Medical

Science, Kanazawa University, 5-10-80 Kodachino, Kanazawa,

Ishikawa 920-0942, Japan

123

Ann Nucl Med (2013) 27:808–821

DOI 10.1007/s12149-013-0750-4

Introduction

The positron emission tomography (PET) radiopharma-

ceutical 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is

currently used for diagnostic imaging of a variety of tumors

[1]. However, 18F-FDG is known to accumulate in normal

structures and in sites of inflammation, reducing its speci-

ficity [2–5]. Several investigators have reported that18F-FDG PET performed to assess for malignancy showed

20–50 % false positive results, with the higher false positive

rates found in geographical areas of endemic granuloma-

tous diseases, such as histoplasmosis or tuberculosis [5–8].

A variety of new tracers has been introduced in order to

overcome these limitations [9–11]. Amino acid tracers are

one promising category. 11C-methionine (11C-MET) has

been extensively investigated, though with several draw-

backs being revealed [12]. 11C-MET is not stable in vivo,

becoming trans-methylated, and losing its 11C moiety as

it is metabolized [13]. Several studies have shown that11C-MET is not tumor-specific, and accumulates in some

inflammatory diseases, such as sarcoidosis [14, 15].

[N-methyl-11C]a-methylaminoisobutyric acid (11C-MeAIB)

is an artificial amino acid PET tracer, which, unlike 11C-MET,

is metabolically stable in vivo [16, 17]. It has been shown

that 11C-MeAIB is a useful tracer for measurement of

amino acid uptake by skeletal muscle, and in the diagnosis

of malignant lymphoma and head and neck cancers [16, 18,

19]. The utility of 11C-MeAIB PET in the diagnosis of

chest malignancies has not yet been evaluated.

The purpose of this study is to investigate the efficacy of11C-MeAIB PET or PET/CT as a diagnostic tool for dis-

tinguishing between malignancies and inflammatory dis-

eases, when CT or 18F-FDG PET or PET/CT shows

equivocal findings.

Materials and methods

Patients

From March 2009 to September 2012, 59 cases (57

patients; male: 35, female: 22; ranging from 28 to 88 years;

mean age: 65.5 ± 12.3) (Table 1, left) of new chest lesions

detected by CT scan (21 patients had lung lesions only, 20

patients had mediastinal lesions only, and 18 patients had

both lesions) were selected. Two patients received this

study protocol twice with 1 year interval or more. Each

patient gave written informed consent. The tracer study

was approved by our institutional review boards, the

Human Study Committee (approval number: #36-04, Mar.

25, 2009) and the Committee for the Clinical Use of Short-

Half Life Radioactive Materials (approval number: #2008-

01, Nov. 28, 2008).

Inclusion criteria were: (1) a new chest lesion detected

on CT scan, suspicious for malignancy, (2) CT (and18F-FDG PET or PET/CT) showing equivocal findings,

with further evaluation requested by referring pulmonolo-

gists, and (3) disease confirmed by pathology, or clinical

follow-up for more than 12 months after PET studies.

Exclusion criteria were: (1) malignant or inflammatory

lesions which received treatment within 6 months before18F-FDG PET or PET/CT, (2) apparent direct invasion of

neighboring organs, (3) apparent extra-pulmonary meta-

static lesions, and (4) patients who refused to undergo11C-MeAIB PET or PET/CT. Baseline diseases or detailed

background of clinical conditions are shown in Table 1

(left).

The CT scans had been performed as routine clinical

studies with a multi-detector row CT scanner, Aquilion 16

(Toshiba, Tokyo, Japan). All patients subsequently under-

went both 18F-FDG and 11C-MeAIB PET or PET/CT

within 2 weeks of the CT.

PET studies

18F was produced by 18O(p, n) 18F reaction. 18F-FDG was

synthesized by the nucleophilic substitution method using

an 18F-FDG-synthesizing instrument F-100 (SHI, Tokyo,

Japan) and a cyclotron, CYPRIS-325R (SHI, Tokyo,

Japan). Otherwise, 18F-FDG was purchased commercially

from Nihon-Medi-Physics (Tokyo, Japan).

Production of 11C-MeAIB was based on the method

proposed by Nagren et al. [20]. The patients fasted for

more than 5 h before the injection of 18F-FDG or 11C-

MeAIB. Blood glucose levels were measured before the

injection of 18F-FDG, and all the patients showed levels of

B150 mg/dL (95.2 ± 13.1 mg/dL). All subjects underwent

two separate scans, one following an intravenous injection

of 18FDG (298 ± 68 MBq), and another after the intrave-

nous injection of 11C-MeAIB (512 ± 50 MBq). Whole-

body PET image acquisition commenced 50 min after 18F-

FDG and 20 min after 11C-MeAIB injection. PET scans

were performed either by a whole-body PET scanner, GE

Advance (GE Healthcare, Waukesha WI, USA), or by a

whole-body PET/CT scanner, Siemens True Point Bio-

graph 16 (Siemens/CTI, Erlangen, Germany).

Image analysis

Visual analysis of each lesion on the two PET scans was

performed by two experienced nuclear medicine physicians

(RN, TH) provided with clinical information including CT

scans and tumor markers. All lesions were graded as

positive or negative by consensus of two readers. If a

nodule showed similar or lower uptake than that in the

upper to middle normal mediastinal tissues, uptake was

Ann Nucl Med (2013) 27:808–821 809

123

defined as negative. If a nodule showed higher uptake than

that of the normal mediastinal tissues, its uptake was

defined as positive. However, high 18F-FDG uptake was

sometimes defined as negative in cases of sarcoidosis and

other benign entities with a characteristic pattern by con-

sensus of two readers.

Semi-quantitative analysis of 18F-FDG and 11C-MeAIB

uptake was also performed. Regions of interest (ROIs) were

defined on the target lesions in the transaxial tomograms of

PET-only images. PET-to-CT co-registration was per-

formed using automatic rigid/non-rigid body-deformable

fusion software: Quantiva/BodyGuide (Tomographix IP

Ltd., Toronto, Canada). In PET/CT scans, ROIs were

defined and confirmed on the fused PET and CT images

(hereafter all scans will be referred to as PET/CT scans,

since PET images were always fused to CT images). The

standardized uptake value (SUV) was calculated as follows:

SUV¼ C kBq=mlð ÞID kBqð Þ=body weight gð Þ

where C represents tissue activity concentration measured

by PET and ID represents the injected dose. The mean

SUV of the normal tissue (lung field and mediastinum) was

defined as the SUVmean. The highest SUV of the lesion

was defined as the SUVmax.

Statistics

All values are expressed as mean ± SD. All the statistical

analyses were performed using statistical software, JMP 8J

Table 1 Characteristics of Total 57 Patients [59 PET studies (2 patients received 2 series of PET studies with [5 months interval)] and 80

lesions

Age (years) Final diagnosis (lesion-based), n (%)

Mean ± SD 65.5 ± 12.3

Range 28–88 Pulmonary nodules in the lung fields: (n = 42)

Gender, n (%) Lung cancer 18 (43 %)

Male 35 (61 %) Adenocarcinoma 12 (29 %)

Female 22 (39 %) Squamous cell carcinoma 3 (7 %)

Small cell carcinoma 2 (5 %)

Purpose of total 57 PET study, n (%) Large cell carcinoma 1 (2 %)

Evaluation of lung nodule(s) 22 (37 %) Other malignancies (post-treated) 4 (10 %)

Evaluation of mediastinal nodule(s) 20 (34 %) Mesothelioma 2 (5 %)

Evaluation of both 17 (29 %) Colorectal cancer 1 (2 %)

Lymphoma 1 (2 %)

Baseline diseases, n (%) Non-malignant diseases 20 (48 %)

None, newly developed lung nodule 30 (51 %) Non-specific inflammatory changes 13 (31 %)

None, newly developed mediastinal lesion(s) 20 (34 %) Sarcoid nodule 5 (12 %)

Newly developed chest lesion(s) Abscess 2 (5 %)

in the follow-up of other malignancies (post operated) 9 (15 %)

Gastric malignant lymphoma 2 (3 %) Hilar and mediastinal nodules: (n = 38)

Colorectal cancer 3 (5 %) Malignant diseases 10 (26 %)

Gastric cancer 2 (3 %) Adenocarcinoma 4 (11 %)

Esophageal cancer 1 (2 %) Squamous cell carcinoma 3 (8 %)

Urinary bladder cancer 1 (2 %) Small cell carcinoma 1 (3 %)

Mesothelioma 1 (3 %)

Final confirmation of 57 PET diagnosis Lymphoma 1 (3 %)

Pathological confirmation 35 (59 %) Non-malignant diseases 28 (74 %)

Surgical resection (including VATS**) 17 (29 %) Sarcoidosis 15 (39 %)

Biopsy at bronchoscopy 6 (10 %) Non-specific inflammatory changes 9 (24 %)

Biopsy at thoracoscopy 3 (5 %) IgG4 related disease 2 (5 %)

CT-guided biopsy 1 (2 %) Squamous cell papilloma 1 (3 %)

Resection or biopsy of superficial lymph node 7 (12 %) Tubercular nodule 1 (3 %)

Sputum culture 1 (2 %)

Clinical follow-up ([12 months) 24 (42/1 %)

810 Ann Nucl Med (2013) 27:808–821

123

version (SAS Institute, Cary NC, USA), in which p values

\0.05 were considered statistically significant. A com-

parison between each group was analyzed by the Wilcoxon

score for unpaired data. Receiver operating characteristic

curve (ROC) analyses for the diagnostic accuracy in 11C-

MeAIB PET/CT and 18F-FDG PET/CT were generated

using GraphPad Prism ver. 5.0 (GraphPad software, San

Diego CA, USA). A comparison of SUVmax between 11C-

MeAIB and 18F-FDG in each lesion was analyzed by the

Logistic regression.

Results

Table 1 summarizes the patient characteristics. The final

diagnosis was confirmed pathologically by surgical resec-

tion in 17 cases, while biopsy at bronchoscopy, thoracos-

copy, and CT-guided biopsy confirmed diagnosis in 10

cases. Resection or biopsy of lymph nodes at neck or supra-

clavicular area was performed in seven cases. Clinical

diagnosis was determined by follow-up for at least

12 months in 24 cases. Of the 59 cases in the present study,

there were 22 malignant and 20 benign pulmonary nodules

in the lungs and 10 malignant and 28 benign mediastinal

lesions.

Figure 1 shows a typical malignant case, while Fig. 2

shows a typical benign case; in this instance, sarcoidosis. In

Fig. 3, a 18F-FDG-strongly positive lung nodule was

diagnosed as sarcoidosis. Equivocal findings of metastatic

colon cancer are shown in Fig. 4.

Semi-quantitative analysis of 18FDG uptake

and 11C-MeAIB uptake

The average SUVmax and SUVmean for 18F-FDG and11C-MeAIB uptake in normal lung and mediastinum are

shown in Table 2. The average SUVmax of 18F-FDG in

malignant lesions was significantly higher than that in

benign lesions for 42 pulmonary nodules, while not sig-

nificantly different for 38 benign and malignant mediasti-

nal lesions. There was a wide overlap in 18F-FDG uptake

between malignant and benign chest diseases, resulting in

A

DC

B

Fig. 1 A case of lung cancer. Fifty-nine-year-old asymptomatic male

patient. Screening chest X-ray showed abnormal density in the left

upper lung zone. The patient underwent a contrast-enhanced chest CT

scan, which revealed a nodule in the left apex (a) with probably lymph

node (ln) metastasis in the left hilum (b). Bronchoscopic biopsy

revealed squamous cell carcinoma (SCC). Both 18F-FDG PET and11C-MeAIB PET (c, d: MIP image) showed high accumulation in the

left upper lobe lesion (SUVmax = 13.2 for 18FDG, 6.3 for 11C-

MeAIB, arrows) and left hilar ln (SUVmax = 21.9 for 18F-FDG, 11.5

for 11C-MeAIB, arrowheads). It should be noted that 18F-FDG uptake

was relatively greater in the periphery than that of 11C-MeAIB. It was

confirmed as concomitant inflammatory changes in the tissue

surrounding the lesion. A small bone metastasis was also suspected

in the right scapula (not pathologically confirmed)

Ann Nucl Med (2013) 27:808–821 811

123

many false positive cases on 18F-FDG PET/CT, especially

in mediastinal lesions.

The average SUVmax of malignant lesions with11C-MeAIB PET/CT was significantly lower than that for18F-FDG PET/CT. On the other hand, 11C-MeAIB uptake

by malignant and benign lesions showed greater statistical

differences both among pulmonary nodules and mediasti-

nal lesions.

Figure 5 shows the result of ROC analyses for 18F-FDG

and 11C-MeAIB, in which the diagnostic accuracies were

obtained from the SUVmax values of each tumor in both

PET/CT studies. An SUVmax = 3.0 was used as the

threshold for 18F-FDG diagnosis. Other thresholds (SUV-

max = 2.0, 2.5, 3.5, 4.0) gave similar or worse diagnostic

results. In 11C-MeAIB PET/CT studies, an SUVmax = 2.0

was used as the optimum threshold. 11C-MeAIB scans

showed a higher value than 18F-FDG scans both in patient-

based (Fig. 5) and lesion-based diagnoses (not shown).

Patient-based diagnostic results

Visual diagnosis of 18FDG and 11C-MeAIB on a per-

patient basis in 59 cases is shown in Table 3 (top). The

accuracy of 18FDG was 72.9 %, which was better than that

from semi-quantitative analysis. Although 18FDG uptake

was often equivocally positive, the final diagnosis was

judged as true negative in many benign or inflammatory

cases because of the analysis of pattern and location of the18F-FDG uptake. Fifteen false positive cases with 18F-FDG

were as follows: granulomatous inflammatory lung nodules

A

CB D

E

Fig. 2 A case of sarcoidosis. Forty-four-year-old asymptomatic

female patient. She had been followed as an outpatient after complete

remission (more than 1 year previously) of malignant abdominal

lymphoma (post-chemotherapy). She had no history of sarcoidosis or

uveitis. The patient underwent chest CT scan (a), which revealed

multiple nodules (arrows) in the middle mediastinum. 18F-FDG PET

(b: MIP image) showed high accumulation in these lesions (SUV-

max = 6.0 for the highest uptake in right hilar lesion), but there was

no other lesions in the body. 11C-MeAIB PET (c: MIP image) showed

no accumulation in these lesions (SUVmax = 1.8, with the highest

uptake in the mediastinum). Thoracoscopic biopsy revealed sarcoid-

osis (d: low magnification, e: high magnification)

812 Ann Nucl Med (2013) 27:808–821

123

and mediastinal lymphadenopathy confirmed by surgical

resection (n = 6), mediastinal sarcoid lymphadenopathy

by lymph node biopsy (n = 5), mediastinal IgG4-related

lymphadenopathy by lymph node biopsy (n = 1), and non-

specific inflammatory change followed for more than

12 months (n = 3). The accuracy of 11C-MeAIB was

81.4 %. Ten false positive cases with 11C-MeAIB were as

follows: granulomatous inflammatory lung nodules and

mediastinal lymphadenopathy confirmed by surgical

resection (n = 4), mediastinal sarcoid lymphadenopathy

by lymph node biopsy (n = 3), mediastinal IgG4-related

lymphadenopathy by lymph node biopsy (n = 1), and non-

specific inflammatory change followed for more than

12 months (n = 2). Nine of these 11C-MeAIB false posi-

tive cases were also false positive with 18F-FDG. One false

negative case was of metastatic colon cancer, which was

also false negative in 18F-FDG PET images (Fig. 4).

In the semi-quantitative diagnoses (59 cases) with

SUVmax = 3.0 cut-off value, the accuracy of 18F-FDG

PET/CT was 47.5 %, in which there were many false

positive results as compared with those at visual diagnosis

(Table 3 bottom). There were two false negative cases with18F-FDG PET/CT; both were papillary adenocarcinomas

with ground-glass opacity (n = 2, diameter: 25 and

25 mm, SUVmax: 1.89 and 2.00). The accuracy of 11C-

MeAIB PET/CT with SUVmax = 2.0 cut-off value was

74.6 %. There were 13 false positive cases and 2 false

negative cases. The false positive cases were as follows:

granulomatous inflammatory mediastinal lymphadenopa-

thy confirmed by surgical resection (n = 4), mediastinal

sarcoid lymphadenopathy by lymph node biopsy (n = 3),

IgG4-related syndrome (n = 1), and non-specific inflam-

matory change followed for more than 12 months (n = 5).

The two false negative cases were papillary adenocarci-

nomas with ground-glass opacity (n = 2, diameter: 25 and

30 mm, SUVmax: 1.74 and 1.93). The former one was also

false negative case with 18FDG, but the latter one was true

positive with 18FDG.

A

CB

D

FE

Fig. 3 A case of sarcoidosis with lung nodule and mediastinal

lesions. Sixty-three-year-old asymptomatic male patient. He had been

followed as an outpatient for mediastinal sarcoidosis in another

hospital. A new lung nodule was detected on CT scan and he was

referred to our hospital. Both 18F-FDG PET/CT and 11C-MeAIB PET/

CT were performed (a, d: MIP image). There was high 18F-FDG

accumulation (SUVmax = 12.3) in the right lower lobe lesion (b: CT,

c: PET/CT image), multiple mediastinal lesions, including right hilar

lymph nodes (SUVmax = 7.6, arrowheads) and also in the upper

abdominal lymph nodes (cardiac involvement was also indicated and

confirmed later). 11C-MeAIB PET/CT showed very low accumulation

(SUVmax = 1.7) in the right lower lobe lesion (e: CT, f: PET/CT

image) (SUVmax = 1.7), multiple mediastinal lesions, including left

hilar lymph nodes (SUVmax = 1.7, arrowheads), and also in the

upper abdominal lymph nodes. Follow-up CT scan revealed shrinkage

of lung nodule, and the diagnosis of sarcoidosis was confirmed

Ann Nucl Med (2013) 27:808–821 813

123

Lesion-based semi-quantitative diagnostic results

In the differential diagnosis of pulmonary nodules with

SUVmax = 3.0 cut-off value, the accuracy of 18F-FDG

PET/CT was 65.0 % (Table 4 top). The accuracy of 18F-

FDG PET/CT for the diagnosis of mediastinal nodules

(Table 4 bottom) was only 31.6 %. There were 26 cases of

false positive results with 18F-FDG PET/CT, and the

positive predictive value was only 27.8 %. 11C-MeAIB

PET/CT showed better accuracy. The accuracy of11C-MeAIB with SUVmax = 2.0 cut-off value for pul-

monary nodules and mediastinal nodules was 76.2 and

76.3 %, respectively. In mediastinal nodules, there were

only nine cases of false positive results, for a positive

predictive value of 52.6 %.

Discussion

Several amino acid compounds have been suggested as

feasible candidates for oncologic PET tracers which can

overcome the drawbacks of 18F-FDG. 11C-MeAIB is con-

sidered to be one of the most promising amino acid ra-

diotracers in clinical oncology. To our knowledge, the

present study is the first to evaluate the clinical application

of 11C-MeAIB PET-to-chest lesion diagnosis.

Our principal finding is that the diagnostic results of11C-MeAIB PET/CT were better than those of 18F-FDG

PET/CT, especially for the identification of non-malignant

lesions. Table 3 clearly reveals the higher specificity of11C-MeAIB PET/CT in these cases. In the evaluation of

mediastinal lesions, 11C-MeAIB PET/CT showed 67.9 %

A

CB

D

E

Fig. 4 A case of metastatic colon cancer. Sixty-two year-old

asymptomatic female patient and without elevated tumor markers.

She had been followed as an outpatient after the resection of primary

advanced colon adenocarcinoma with mucin secretion. In the follow-

up period (1 year after surgery), the patient underwent a contrast-

enhanced chest CT scan (a), which revealed a small lung nodule in the

left apex. Both 18FDG and 11C-MeAIB PET showed faint

accumulation in the left upper lobe lesion (SUVmax = 3.12 for 18F-

FDG, 2.06 for 11C-MeAIB). Both 18F-FDG and 11C-MeAIB PET

diagnoses were ‘‘equivocal’’ (visual diagnosis: negative, quantitative

diagnosis: positive) (b, c). After close follow-up by CT scan and

tumor markers, she underwent left upper lobe resection, and this

lesion was confirmed as metastatic colon cancer with mucin secretion

by pathology (d: low magnification, e: high magnification)

814 Ann Nucl Med (2013) 27:808–821

123

specificity in lesion-based semi-quantitative diagnosis,

while 18F-FDG PET/CT’s specificity was only 7.1 %

(Table 4). The low positive predictive value (27.8 %) of18F-FDG PET/CT confirms that positive uptake of18F-FDG is not reliably diagnostic of malignancy. We

believe that 11C-MeAIB PET/CT would make a great

contribution in the diagnosis of patients with pulmonary

nodules or mediastinal lesions, when CT and 18F-FDG

PET/CT shows equivocal findings.

It should be noted that 11C-MeAIB PET/CT displayed

high diagnostic accuracy in the evaluation of sarcoidosis.

There were 20 sarcoid lesions in 14 patients and the average

lesion 18F-FDG SUVmax was 7.3 ± 4.5, while that of 11C-

MeAIB was 1.8 ± 0.7 (Table 5). Visual diagnosis with 18F-

FDG PET/CT showed false positives in six patients, while

those with 11C-MeAIB PET/CT showed false positives in

three patients. Although 18F-FDG PET/CT can diagnose

sarcoidosis by the specific uptake pattern of hilar and

mediastinal lesions, sarcoidosis can form pulmonary nod-

ules as well, and those lesions can be difficult to distinguish

from malignancies. In addition, malignancy is often

observed synchronously or metachronously in patients with

sarcoidosis. In the present study, there were five pulmonary

Table 2 Quantitative analysis of total 42 pulmonary lesions and 38 mediastinal lesions

n.s. not significant

* p \ 0.05, § p \ 0.005, §§ p \ 0.0005

Fig. 5 Receiver operating characteristic curve (ROC) analyses for

the diagnostic accuracy of 11C-MeAIB and 18F-FDG using semi-

quantitative analysis. The area under the curve (AUC) value for 11C-

MeAIB PET/CT was 0.85 with standard error: 0.039, 95 % CI:

0.77–0.92 and p \ 0.0001. AUC for 18F-FDG PET/CT was 0.70 with

standard error: 0.056, 95 % CI: 0.60–0.82 and p \ 0.001. These

analyses indicated the better diagnostic accuracy of 11C-MeAIB for

chest diseases (p \ 0.05)

Ann Nucl Med (2013) 27:808–821 815

123

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tsw

ith

mal

ign

ant

lesi

on

s,

n=

22

Pat

ien

tsw

ith

ben

ign

lesi

on

s,

n=

37

FD

G:

po

siti

ve

20

29

40

.8P

PV

(%)

MeA

IB:

po

siti

ve

20

13

60

.6P

PV

(%)

FD

G:

neg

ativ

e2

88

0.0

NP

V(%

)M

eAIB

:n

egat

ive

22

49

2.3

NP

V(%

)

90

.92

1.6

47

.59

0.9

64

.97

4.6

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

PP

Vp

osi

tiv

ep

red

icti

ve

val

ue,

NP

Vn

egat

ive

pre

dic

tiv

ev

alu

e

816 Ann Nucl Med (2013) 27:808–821

123

Ta

ble

4L

esio

n-b

ased

dia

gn

ost

icre

sult

so

fF

DG

-an

dM

eAIB

-PE

T(P

ET

/CT

)u

sin

gse

mi-

qu

anti

tati

ve

anal

ysi

s

Pu

lmo

nar

yn

od

ule

sin

the

lun

gfi

eld

s:(n

=4

2)

FD

G(S

UV

max

=3

.0as

thre

sho

ld)

MeA

IB(S

UV

max

-2.0

asth

resh

old

)

Mal

ign

ant

lesi

on

s,

(n=

22

)

Ben

ign

lesi

on

s,(n

=2

0)

Mal

ign

ant

lesi

on

s,

(n=

22

)

Ben

ign

lesi

on

s,

(n=

20

)

FD

G:

po

siti

ve

20

12

62

.5P

PV

*(%

)M

eAIB

:p

osi

tiv

e2

08

71

.4P

PV

*(%

)

FD

G:

neg

ativ

e2

67

5.0

NP

V*

*(%

)M

eAIB

:n

egat

ive

21

28

5.7

NP

V*

*(%

)

90

.93

3.3

65

.09

0.9

60

.07

6.2

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

Hil

aran

dm

edia

stin

aln

od

ule

s:(n

=3

8)

FD

G(S

UV

max

=3

.0as

thre

sho

ld)

MeA

IB(S

UV

max

-2.0

asth

resh

old

)

Mal

ign

ant

lesi

on

s,

(n=

10

)

Ben

ign

lesi

on

s,

(n=

28

)

Mal

ign

ant

lesi

on

s,

(n=

10

)

Ben

ign

lesi

on

s,

(n=

28

)

FD

G:

po

siti

ve

10

26

27

.8P

PV

*(%

)M

eAIB

:p

osi

tiv

e1

09

52

.6P

PV

*(%

)

FD

G:

neg

ativ

e0

21

00

.0N

PV

**

(%)

MeA

IB:

neg

ativ

e0

19

10

0.0

NP

V*

*(%

)

10

0.0

7.1

31

.61

00

.06

7.9

76

.3

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

Sen

siti

vit

y(%

)S

pec

ifici

ty(%

)A

ccu

racy

(%)

*P

PV

po

siti

ve

pre

dic

tiv

ev

alu

e,*

*N

PV

neg

ativ

ep

red

icti

ve

val

ue

Ann Nucl Med (2013) 27:808–821 817

123

Ta

ble

5P

atie

nt

char

acte

rist

ics

(sar

coid

osi

s)

Pat

ien

t

no

.

Age/

sex

Purp

ose

of

PE

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Oth

er

dis

ease

s

AC

Eb

IU/L

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tra-

pu

lmo

nar

y

invo

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ent

of

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oid

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ent

for

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oid

osi

s

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ho

log

ical

Co

nfi

rmat

ion

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get

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on

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sis

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gnosi

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ual

dia

gn

osi

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Vm

axQ

uan

tita

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e

dia

gn

osi

scV

isual

dia

gn

osi

s

SU

Vm

axQ

uan

tita

tiv

e

dia

gn

osi

sd

14

8/F

P&

MN

on

e2

1.3

No

ne

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t trea

ted

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llow

-up

mo

reth

an

1y

ear

Med

iast

inal

lesi

on

s

TN

6.8

FP

TN

2.4

FP

Pu

lmo

nar

y

lesi

on

TN

1.3

TN

TN

0.6

TN

25

8/M

P&

MU

lcer

ativ

e

coli

tis

7.0

No

ne

No

t trea

ted

Fo

llow

-up

mo

reth

an

1y

ear

Med

iast

inal

lesi

on

s

TN

6.8

FP

TN

1.5

TN

Pu

lmo

nar

y

lesi

on

TN

0.8

TN

TN

0.7

TN

36

1/F

P&

MN

on

e1

3.3

Ey

eS

tero

id

eye

dro

p

Bio

psy

at

tho

raco

sco

py

Med

iast

inal

lesi

on

s

FP

6.4

FP

TN

1.8

TN

Pu

lmo

nar

y

lesi

on

TN

1.3

TN

TN

0.7

TN

46

3/M (F

ig.

3)

P&

MD

iab

etes

(co

ntr

oll

ed)

31

.9H

eart

(dia

gn

ose

db

y

PE

T)

No

t trea

ted

Bio

psy

at

tho

raco

sco

py

Med

iast

inal

lesi

on

s

FP

7.6

FP

TN

1.7

TN

Pu

lmo

nar

y

lesi

on

FP

12

.3F

PT

N1

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N

53

6/M

P&

MN

on

e1

3.4

Su

per

fici

al

lym

ph

no

des

No

t trea

ted

Bio

psy

at

sup

erfi

cial

lym

ph

no

de

Med

iast

inal

lesi

on

s

FP

8.1

FP

FP

3.2

FP

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lmo

nar

y

lesi

on

FP

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PF

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66

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astr

ic

mal

ign

ant

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a

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llow

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mo

reth

an

1y

ear

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iast

inal

lesi

on

s

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iast

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ted

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sup

erfi

cial

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no

de

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iast

inal

lesi

on

s

FP

17

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P3

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P

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1/M

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olo

np

oly

ps

24

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on

eN

ot trea

ted

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llow

-up

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reth

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1y

ear

Med

iast

inal

lesi

on

s

TN

5.7

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1.9

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95

0/M

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on

e1

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ne

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t trea

ted

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psy

at

tho

raco

sco

py

Med

iast

inal

lesi

on

s

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10

70

/FM

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gin

a

pec

tori

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on

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ot trea

ted

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llow

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reth

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ear

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iast

inal

lesi

on

s

TN

2.8

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818 Ann Nucl Med (2013) 27:808–821

123

Ta

ble

5co

nti

nu

ed

Pat

ien

t

no

.

Age/

sex

Purp

ose

of

PE

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er

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ease

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AC

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nar

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olv

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oid

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ent

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ho

log

ical

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nfi

rmat

ion

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get

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on

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ET

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iag

no

sis

11C

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IBd

iagn

osi

s

Vis

ual

dia

gn

osi

s

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Vm

axQ

uan

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e

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gn

osi

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isual

dia

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axQ

uan

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e

dia

gn

osi

sd

11

64

/FM

No

ne

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on

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llo

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p

mo

reth

an

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iast

inal

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on

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77

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ye

Ste

roid

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dro

p

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at

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raco

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py

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iast

inal

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71

/FM

No

ne

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ted

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reth

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44

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ic

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ant

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at

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Les

ion

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ecifi

city

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ased

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ost

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orm

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/L)

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shold

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Thre

shold

:S

UV

max

=2

.0

Ann Nucl Med (2013) 27:808–821 819

123

lesions (all of them finally confirmed as benign) in five

patients with sarcoidosis. In these cases, 11C-MeAIB PET/

CT played a useful diagnostic role (Fig. 3). Since 11C-MET

accumulates in sarcoidosis [14, 15], it is suggested that 11C-

MeAIB may be superior to 11C-MET in the differentiation

of sarcoidosis from malignancy. Our result is compatible

with previous studies using other amino acid PET tracers,

such as [18F]-methyltyrosine (18F-FMT) [21]. Kaira et al.

suggested in their report that the use of 18F-FMT PET in

combination with 18F-FDG PET may be effective for this

purpose. In terms of biological mechanism, it is not fully

understood why 11C-MET and the other amino acid PET

tracers (11C-MeAIB and 18F-FMT) show different uptake

patterns in sarcoidosis. One of the conceivable mechanisms

for the low uptake in sarcoidosis lesions of 11C-MeAIB and18FMT is that these PET tracers, as artificial amino acids,

are not metabolized in vivo [16, 22]. Concerning in vivo

instability of 11C-MET, inflammatory lesion can be mis-

diagnosed by 11C-MET PET because of its non-specific

accumulation of free 11C in blood when an inflammatory

lesion shows hypervascularity. Comparative study of these

amino acid PET tracers should be further evaluated.

In the diagnosis of malignancy, the sensitivity of18F-FDG and 11C-MeAIB based on semi-quantitative

patient-based diagnosis showed the same values (90.9 %)

(Table 4). In addition, the uptake of 11C-MeAIB correlated

well with 18F-FDG uptake and there were basically no

discrepant cases (Fig. 6). 18F-FDG SUVs in malignant

cases was usually two to three times higher than those of11C. In previous studies using 11C-MET and 18F-FMT,11C-MET and 18F-FMT SUVs were also two to three times

lower than those of 18FDG [21, 23–25]. This may be a

common drawback of amino acid PET tracers. Although

our group included several different types of lung cancers,

such as adenocarcinoma, squamous cell carcinoma, and

small cell carcinoma, there was no significant difference in

the uptake intensity of 11C-MeAIB among the different

histological types. It is not what we anticipated for11C-MeAIB PET/CT’s use as a predictor of therapeutic

effect, because amino acid transporters are known to work

as carriers of chemotherapeutic agents, such as cisplatin,

methotrexate, taxol, and melphalan [26–28]. The role of11C-MeAIB PET/CT as an imaging modality for patient-

tailored medicine is unknown. Further study of pre- and

post-chemotherapeutic 11C-MeAIB PET or PET/CT is

needed.

Another drawback of 11C-MeAIB is its high physio-

logical uptake by liver. It means that 11C-MeAIB PET/CT

cannot be performed as a first-choice diagnostic modality

in the evaluation of chest malignancies, because liver

metastasis is common in lung cancer. Therefore,11C-MeAIB PET or PET/CT cannot be performed as a

study for staging of advanced lung cancer. This is why we

focused our study only on the differential diagnosis in chest

diseases, and excluded cases with apparent distant metas-

tasis and direct invasion of neighboring organs.

Conclusions

11C-MeAIB PET/CT was useful in the differential diag-

nosis of pulmonary and mediastinal mass lesions found on

CT. 11C-MeAIB PET or PET/CT showed higher specificity

than that of 18F-FDG PET/CT in differentiating between

benign and malignant disease. Our data suggest that the

combination of 18F-FDG and 11C-MeAIB may improve the

evaluation of chest lesions, when CT and 18F-FDG PET/CT

are equivocal.

Acknowledgments This study was supported by two categories of

the Grants-in-Aid for Scientific Research programmed by the Japan

Society for the Promotion of Science (JSPS), Challenging Exploratory

Fig. 6 Relationship between SUVmax of 11C-MeAIB and that of18F-FDG of each lesion in both PET study using Logistic regression.

In malignant lesions, SUVmax of 11C-MeAIB shows a significant

linear relationship with that of 18F-FDG (p \ 0.0001, R2 = 0.406).

On the other hand, that of 11C-MeAIB also shows a linear correlation

with that of 18F-FDG but not significant in benign lesions (p = 0.055,

R2 = 0.078)

820 Ann Nucl Med (2013) 27:808–821

123

Research (Grant #50324629, 2009–2010), and Scientific Research

(B) (Grant #23300360, 2011–2013).

Conflict of interest The authors report no conflict of interest.

Open Access This article is distributed under the terms of the

Creative Commons Attribution License which permits any use, dis-

tribution, and reproduction in any medium, provided the original

author(s) and the source are credited.

References

1. Poeppel TD, Krause BJ, Heusner TA, Boy C, Bockisch A, Ant-

och G. PET/CT for the staging and follow-up of patients with

malignancies. Eur J Radiol. 2009;70(3):382–92.

2. Metser U, Even-Sapir E. Increased (18)F-fluorodeoxyglucose

uptake in benign, nonphysiologic lesions found on whole-body

positron emission tomography/computed tomography (PET/CT):

accumulated data from four years of experience with PET/CT.

Semin Nucl Med. 2007;37(3):206–22.

3. Higashi T, Saga T, Nakamoto Y, Ishimori T, Fujimoto K, Doi R,

Imamura M, Konishi J. Diagnosis of pancreatic cancer using

fluorine-18 fluorodeoxyglucose positron emission tomography

(FDG PET)—usefulness and limitations in ‘‘clinical reality’’. Ann

Nucl Med. 2003;17(4):261–79 (review).

4. Shreve PD, Anzai Y, Wahl RL. Pitfalls in oncologic diagnosis

with FDG PET imaging: physiologic and benign variants.

Radiographics. 1999;19(1):61–77 (review).

5. Chang JM, Lee HJ, Goo JM, Lee HY, Lee JJ, Chung JK, Im JG.

False positive and false negative FDG-PET scans in various

thoracic diseases. Korean J Radiol. 2006;7:57–69 (review).

6. Hu M, Han A, Xing L, Yang W, Fu Z, Huang C, et al. Value of

dual-time-point FDG PET/CT for mediastinal nodal staging in

non-small-cell lung cancer patients with lung comorbidity. Clin

Nucl Med. 2011;36:429–33.

7. Deppen S, Putnam JB Jr, Andrade G, Speroff T, Nesbitt JC,

Lambright ES, et al. Accuracy of FDG-PET to diagnose lung

cancer in a region of endemic granulomatous disease. Ann

Thorac Surg. 2011;92:428–32.

8. Lee JW, Kim BS, Lee DS, Chung JK, Lee MC, Kim S, et al. 18F-

FDG PET/CT in mediastinal lymph node staging of non-small-

cell lung cancer in a tuberculosis-endemic country: consideration

of lymph node calcification and distribution pattern to improve

specificity. Eur J Nucl Med Mol Imaging. 2009;36:1794–802.

9. Antoni G, Langstrom B. Radiopharmaceuticals: molecular

imaging using positron emission tomography. Handb Exp Phar-

macol. 2008;(185 Pt 1):177–201. Review.

10. Wadsak W, Mitterhauser M. Basics and principles of radiophar-

maceuticals for PET/CT. Eur J Radiol. 2010;73(3):461–9 (review).

11. Jager PL, Vaalburg W, Pruim J, de Vries EG, Langen KJ, Piers

DA. Radiolabeled amino acids: basic aspects and clinical appli-

cations in oncology. J Nucl Med. 2001;42(3):432–45 (review).

12. Leskinen-Kallio S, Ruotsalainen U, Nagren K, Teras M, Joensuu

H. Uptake of carbon-11-methionine and fluorodeoxyglucose in

non-Hodgkin’s lymphoma: a PET study. J Nucl Med. 1991;32(6):

1211–8.

13. Fujibayashi Y, Kawai K, Yonekura Y, Matsumoto K, Konishi J,

Yokoyama A. Problems of [S-methyl-11C]-L-methionine as a

protein synthesis marker in the pancreas. Ann Nucl Med. 1990;

4(1):29–33.

14. van Waarde A, Jager PL, Ishiwata K, Dierckx RA, Elsinga PH.

Comparison of sigma-ligands and metabolic PET tracers for

differentiating tumor from inflammation. J Nucl Med.

2006;47(1):150–4.

15. Yamada Y, Uchida Y, Tatsumi K, Yamaguchi T, Kimura H,

Kitahara H, et al. Fluorine-18-fluorodeoxyglucose and carbon-11-

methionine evaluation of lymphadenopathy in sarcoidosis. J Nucl

Med. 1998;39(7):1160–6.

16. Sutinen E, Jyrkkio S, Gronroos T, Haaparanta M, Lehikoinen P,

Nagren K. Biodistribution of [11C] methylaminoisobutyric acid, a

tracer for PET studies on system A amino acid transport in vivo.

Eur J Nucl Med. 2001;28(7):847–54.

17. Christensen HN. Role of amino acid transport and countertrans-

port in nutrition and metabolism. Physiol Rev. 1990;70(1):43–77

(review).

18. Asola MR, Virtanen KA, Peltoniemi P, Nagren K, Yu M, Mattila

K, et al. Amino acid uptake in the skeletal muscle measured using

[11C]methylaminoisobutyrate (MEAIB) and PET. Eur J Nucl

Med Mol Imaging. 2002;29(11):1485–91.

19. Sutinen E, Jyrkkio S, Alanen K, Nagren K, Minn H. Uptake of

[N-methyl-11C]alpha-methylaminoisobutyric acid in untreated

head and neck cancer studied by PET. Eur J Nucl Med Mol

Imaging. 2003;30(1):72–7.

20. Nagren K, Sutinen E, Jyrkkio S. [N-methyl-11C]MeAIB, a tracer

for system A amino acid transport: preparation from [11C]Methyl

Triflate and HPLC metabolite analysis of plasma samples after

intravenous administration in man. J Label Cpd Radiopharm.

2000;43:1013–21.

21. Kaira K, Oriuchi N, Otani Y, Yanagitani N, Sunada N, Hisada T,

et al. Diagnostic usefulness of fluorine-18-alpha-methyltyrosine

positron emission tomography in combination with 18F-fluoro-

deoxyglucose in sarcoidosis patients. Chest. 2007;131:1019–27.

22. Inoue T, Tomiyoshi K, Higuchi T, Ahmed K, Sarwar M, Woyagi

K, et al. Biodistribution studies on L-[3-18F] fluoro-alpha-

methyltyrosine: a potential tumor-detecting agent. J Nucl Med.

1998;39:663–7.

23. Kanegae K, Nakano I, Kimura K, Kaji H, Kuge Y, Shiga T, et al.

Comparison of MET-PET and FDG-PET for differentiation

between benign lesions and lung cancer in pneumoconiosis. Ann

Nucl Med. 2007;21(6):331–7.

24. Sasaki M, Kuwabara Y, Yoshida T, Nakagawa M, Koga H,

Hayashi K, et al. Comparison of MET-PET and FDG-PET for

differentiation between benign lesions and malignant tumors of

the lung. Ann Nucl Med. 2001;15(5):425–31.

25. Hsieh HJ, Lin SH, Lin KH, Lee CY, Chang CP, Wang SJ. The

feasibility of 11C-methionine-PET in diagnosis of solitary lung

nodules/masses when compared with 18F-FDG-PET. Ann Nucl

Med. 2008;22(6):533–8.

26. Kashani-Sabet M, Scanlon KJ. Drug selectivity and membrane

transport properties of normal human lymphocytes. Chemother-

apy. 1989;35(5):363–72.

27. del Amo EM, Urtti A, Yliperttula M. Pharmacokinetic role of

L-type amino acid transporters LAT1 and LAT2. Eur J Pharm

Sci. 2008;35(3):161–74.

28. Wu Y, Shen D, Chen Z, Clayton S, Vadgama JV. Taxol induced

apoptosis regulates amino acid transport in breast cancer cells.

Apoptosis. 2007;12(3):593–612.

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